Thrombus refers to a blood clot generated in a blood vessel, in which a protein called fibrinogen is activated, and forms into an insoluble polymer together with platelets, leukocytes and the like while being converted into fibrin, which is solidified on an inner wall of a blood vessel resulting in thrombus. When a body is normal, plasmin functioning to lyse fibrin, a causation for this thrombus, prevents thrombus. However, when plasmin is deficient, fibrin cannot be lysed, whereby thrombus is generated. There are primary hemostasis (platelet aggregation) and secondary hemostasis (blood coagulation) in thrombus. Bleeding is generated by damage of a blood vessel, and platelets are adhered to and aggregated to a hole perforated on a blood vessel wall, thereby temporarily arresting the hemorrhage. This is referred to as primary hemostasis, and the generated thrombus is referred to as primary thrombus. Further, a water-soluble coagulation factor (fibrinogen) in the plasma becomes water-insoluble (fibrin), a net is formed between platelets in a thread-like manner, thereby reinforcing primary thrombus. This is referred to as secondary hemostasis, and generated thrombus is referred to as secondary thrombus.
Platelet aggregation is generated by exposing collagen in a wall by damage of a blood vessel wall, adhering a platelet to exposed collagen, and further aggregating platelets to each other. Mechanism of blood coagulation includes intrinsic blood coagulation and extrinsic blood coagulation. In the intrinsic blood coagulation, a factor XII is contacted with a subendothelial tissue having a negative charge to activate the factor XII, a factor XI is then activated by the activated factor XII, the intrinsic blood coagulation factors being sequentially activated, and finally, fibrinogen, a factor I is subjected to limited degradation by thrombin, an active form of a factor II (prothrombin) to form fibrin, whereby thrombus is formed. The extrinsic blood coagulation is activated by tissue factor and a factor VII, and coagulation progresses from activation of a factor X towards coagulation mechanism common with the intrinsic blood mechanism. Finally, fibrinogen, the factor I is subjected to limited degradation by thrombin, an active form of the factor II (prothrombin) to form fibrin, whereby thrombus is formed.
The formed thrombus is deposited in a blood vessel to reduce a cross-sectional area of a blood vessel, thereby inhibiting the circulation of blood. As a result, there arise some problems that the blood cannot normally supply nutrients and oxygen to cells and tissues, so that waste substances of the cells and the tissues cannot be excreted, whereby toxicity is accumulated, and the like.
Symptom caused by thrombus in a blood vessel is called thrombosis in a broad sense (hereinafter, when simply described as “thrombosis,” this refers to thrombosis in a broad sense), and pathological conditions caused by thrombus are classified into thrombosis in a narrow sense and embolism. Thrombosis in a narrow sense is symptom due to partial or complete occlusion of a blood stream by thrombus at a site where thrombus is formed, and embolism refers to a pathological condition caused by peeling of thrombus from a site where it is formed, movement of thrombus through a blood stream, and partial or complete occlusion of a blood stream by the thrombus at other sites.
The thrombosis as described above is likely to induce a variety of diseases depending upon a site of a blood vessel where thrombus is generated. Among them, particularly, when thrombus is generated in a cerebral blood vessel or a cardiac blood vessel, a serious symptom such as stroke, cerebral hemorrhage, cerebral infarction, cardiac failure, cardiac infarction or cardiac paralysis is generated, thereby causing hemiplegia, or death in a severe case.
Serious thrombus causing these cardiac diseases, cerebral blood vessel diseases and the like is different in mechanism from fibrin thrombus formed under retention of a blood stream. It is thought that the thrombus is formed in the presence of a relatively rapid and ample blood stream such as an artery. Under a blood stream, even when a coagulation factor is activated, since this is diluted with a blood stream, this efficiently does not lead to thrombus formation. However, platelet which is a component adhering to a damaged blood vessel wall, and aggregating to enhance a local concentration plays a more important role in the formation of thrombus.
When a vascular endothelial cell undergoes a disorder and is peeled, collagen of a vascular subendothelial cell tissue is exposed, and crosslinking is formed (adhered) between collagen and von-willebrand factor (vWF: VII factor) receptor (GpIb) by vWF synthesized in a vascular endothelial cell. Further, platelet is activated by an agonist such as thrombin, to be bound with other platelet by a fibrinogen receptor (GpIIb-IIIa) via fibrinogen, thereby causing platelet aggregation, whereby platelet thrombus is formed. Therefore, whether or not formation of cross-linking between collagen and GpIb by vWF, or binding with other platelet by GpIIb-IIIa via fibrinogen can be inhibited is one of important requirements for preventing thrombus formation.
As an agonist which promotes cross-linking formation between the collagen and GpIb by vWF, ristocetin has been known. As an agonist which promotes binding with other platelet by GpIIb-IIIa via fibrinogen, adenosine diphosphate (ADENOSINE 5′DIPHOSPHATE SODIUM: ADP) released from vascular platelet and damaged hemocyte, endothelium or tissue by various substances such as collagen and thrombin has been known.
In the treatment of thrombosis, an antithrombotic agent and a thrombus formation preventing agent for inhibiting formation of thrombus, and a thrombolytic agent for lysing generated thrombus have been mainly studied and developed.
The antithrombotic agent includes an anti-platelet agent and an anti-coagulant. The anti-platelet agent is purposed for inhibiting the function of platelet involved in an early stage of thrombus formation. Numerous orally administrable drugs such as aspirin have been developed, but these drugs have been currently used for preventing recurrence of cerebral infarct, cardiac infarct and the like, and preventing occlusion after various bypass operations. Therefore, these drugs have been used as a thrombus formation preventing drug rather than as a therapeutic agent for thrombosis. As the anti-coagulant, heparin which acts by promoting inhibition of thrombin due to antithrombin III, warfarin which is a coumarin derivative as an oral anti-coagulant have been and the like clinically used. Warfarin inhibits the generation of thrombin by inhibiting vitamin K-dependent γ-carboxylation after the translation in prothrombin synthesis. However, since heparin must be administered parenterally and heparin functions as a cofactor of antithrombin III, heparin has no effect without this inhibitor. Warfarin exhibits effects very slowly, and individual doses must be adjusted by frequent tests. Among these anti-coagulants, there is no anti-coagulant which is specific only for thrombin, and these anti-coagulants also inhibit other serine-protease; therefore, there is a possibility that bleeding is induced unless both doses are accurately adjusted. Recently, eicosapentaenoic acid (EPA), prostacycline (PG12) derivative and the like have also been merchandized. However, since these drugs have no specificity, they also affect on a part other than thrombus in a living body. Therefore, when these drugs remain in a living body, there is a possibility that bleeding or the like is caused. Besides, antithrombotic activity for hirudin, synthetic antithrombin, Ticlopidin or the like has been also reported, but not yet put into practical use.
As the thrombolytic agent, a plasminogen activator such as streptokinase or urokinase has been known, and a therapeutic method of intravenously injecting a plasminogen activator to a patient with thrombus formed to activate a thrombolytic system in a body has been generally used. Although its thrombolytic effect has been verified in some clinical experiments, there is no specificity for thrombus in the same manner as in the antithrombotic agent or the thrombus formation preventing agent, and there is an adverse action such as systemic bleeding during treatment of thrombus. In addition, there has been thought that a tissue-type plasminogen activator (tPA) has high selectivity for thrombus, and is an ideal thrombolytic agent. However, as a result of actual application to clinical treatment, there was still an adverse action such as systemic bleeding with some differences in its extent. In addition, since a half-life in the blood is very short and a sustaining time for drug efficacy is short, a dose must be large in order to sustain the drug efficacy in a body. For this reason, there is a disadvantage that the therapeutic cost is very high as compared to a conventional thrombolytic agent.
Although the medicaments as mentioned above have been used for preventing generation of thrombus, the medicaments do not exhibit remarkable effects in thrombus removal, but induce serious adverse actions. Therefore, recently, studies on a component or a food component which has a function of preventing a disease, or regulating or activating physical condition thorough dietary life rather than a treatment with a medicament have been remarked.
As the food component, a material such as a polyvalent unsaturated fatty acid, glucosamine, or a thin skin of an onion (see, for instance, Patent Publication 1) has been known. However, there is a disadvantage in flavor, nature and the like, so that the material could not be widely applied to foods.
In addition, recently, a patent regarding a kiwi fruit extract (see, for instance, Patent Publication 2) has been published. However, there is a disadvantage that the extract has weak activity in a neutral range.
Further, nattokinase (see, for instance, Patent Publication 3) has been well known. However, although nattokinase has a thrombolytic effect, nattokinase contains vitamin K which contributes to the production of a coagulation factor, at the same time.
Patent Publication 1: Japanese Patent Laid-Open No. 2002-171934 (page 2)
Patent Publication 2: Japanese Patent Laid-Open No. 2003-171294 (pages 2-5)
Patent Publication 3: Japanese Patent Laid-Open No. 2004-65047 (page 3)